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MEK1-induced physiological hypertrophy inhibits chronic post-myocardial infarction remodeling in mice†
Article first published online: 14 NOV 2012
Copyright © 2012 Wiley Periodicals, Inc.
Journal of Cellular Biochemistry
Volume 114, Issue 1, pages 47–55, January 2013
How to Cite
Yeh, C.-C., Malhotra, D., Yang, Y.-L., Xu, Y., Fan, Y., Li, H. and Mann, M. J. (2013), MEK1-induced physiological hypertrophy inhibits chronic post-myocardial infarction remodeling in mice. J. Cell. Biochem., 114: 47–55. doi: 10.1002/jcb.24299
- Issue published online: 14 NOV 2012
- Article first published online: 14 NOV 2012
- Accepted manuscript online: 20 JUL 2012 09:32AM EST
- Manuscript Accepted: 16 JUL 2012
- Manuscript Received: 7 MAY 2012
- National Institutes of Health. Grant Numbers: K08HL079239, R01HL083118
- MYOCARDIAL INFARCTION;
- MAP KINASE;
- MATRIX METALLOPROTEINASE;
Although activation of MEK-ERK signaling is known to be cardioprotective during acute reperfusion injury, the effect of MEK activation on chronic changes in ventricular structure and function during the more complex process of remodeling after myocardial infarction (MI) with or without reperfusion remains uncertain. Four weeks after permanent coronary ligation, LV fractional shorting, preload recruitable stroke work, and end-systolic elastance were all preserved in transgenic mice with CM-specific upregulation of the MEK1-ERK1/2 signaling pathway (MEK1 Tg) compared to wildtype (WT) controls (5.8% decline vs. 17.3%, P < 0.01; 603 ± 98 mmHg vs. 335 ± 98, P < 0.05; 6.14 ± 0.57 mmHg/µl vs. 3.92 ± 0.60, P < 0.05, respectively). Despite similar initial infarct sizes, post-MI remodeling was significantly reduced in MEK1 Tg, demonstrated by reductions in chronic infarct size (28.5 ± 3.1% vs. 47.8 ± 3.2%), myocardial fibrosis (3.98 ± 0.74% vs. 9.27 ± 1.97%) and apoptosis (0.66 ± 0.11% vs. 1.60 ± 0.34%). Higher phosphorylation (i.e., activation) of pro-survival transcription factor STAT3, higher expression of anti-apoptotic protein Bcl2, and higher phosphorylation (i.e., inactivation) of pro-apoptotic BAD were observed in the post-MI remote myocardium of MEK1 Tg. MMP2 activity was higher in MEK1 Tg, while expression of TIMP3 and MMP9 activity were lower in transgenic mice. Beyond any immediate cardioprotective effect, therapeutic activation of MEK1-ERK1/2 signaling during the chronic post-MI period may preserve LV function by increasing the expression of pro-survival factors and by suppressing factors, such as the balance between matrix modulating proteins, that promote pathological remodeling in the remote myocardium. J. Cell. Biochem. 114: 47–55, 2012. © 2012 Wiley Periodicals, Inc.